Evolution and host-adaptation of the mammalian bordetellae

Abstract

B. pertussis and B. parapertussishu both cause pertussis in humans, a highly contagious respiratory disease that is reemerging despite widespread vaccination. B. bronchiseptica, which is closely related to B. pertussis and B. parapertussis, comprises a genetically diverse lineage that has been isolated from many different mammalian hosts and causes chronic respiratory tract diseases. Recently, a third species has been described to cause pertussis-like symptoms, Bordetella holmesii, which has been suggested to be very closely related to B. pertussis.

The origin of the disease pertussis remains an enigma. Pertussis, which has very typical symptoms, was one of the leading causes of childhood mortality prior to the introduction of vaccines in the 1940s and 1950s. However, no historical references have been found in the European literature prior to the Middle Ages. Due to this lack of references and the limited genetic diversity of B. pertussis, it has been assumed that B. pertussis only recently adapted to humans. Previous studies indicated that the human-specific pathogens B. pertussis and B. parapertussishu are derived from distinct B. bronchiseptica-like lineages, although specific ancestral lineages have not yet been described. Based on the complete genome sequences of the mammalian bordetellae, it was suggested that genome reduction was associated with host restriction of B. pertussis and B. parapertussishu, although the key molecular events are unknown. The phylogenetic position of B. holmesii in the Bordetella genus is still controversial, and it is unknown if and how this species emerged as a human pathogen. The goal of this thesis was to elucidate the phylogenetic relationships between Bordetella species that cause respiratory infections in mammals, and to identify genetic factors that are important for adaptation to the human host.

The data presented in this thesis supported a phylogeny with four distinct complexes, representing B. pertussis (complex II), B. parapertussishu (complex III), and two divergent B. bronchiseptica populations (complexes I and IV). Extant members of the newly-identified B. bronchiseptica complex IV were found to circulate predominantly in human populations and cause pertussis-like disease. Calculations of divergence times between complexes suggested that the association of B. pertussis with humans may indeed have been ancient. Comparison of gene content between B. bronchiseptica complex I and IV suggested that B. bronchiseptica complex IV strains have undergone significant genome reduction. We propose that differences in virulence gene content may have been the result of immune-competition between B. pertussis, B. parapertussishu and B. bronchiseptica complex IV in humans. Comparative genomic hybridization data and housekeeping gene sequence data suggested a more distant relationship of B. holmesii to B. pertussis than previously assumed. However, CGH detected a putative pathogenicity island island, containing iron-acquisition genes, that was likely transferred from B. pertussis to B. holmesii and that may have played a role in the emergence of B. holmesii.

Our results provide a refined model for the evolution of Bordetella species that cause respiratory infections in mammalian hosts. It is shown that the human-specific lineages B. pertussis, B. parapertussishu and B. holmesii, all of which may cause pertussis, have evolved through different means and from different lineages. The results presented in this thesis have improved our understanding of how Bordetella species have adapted to the human host, and provide a framework for further studies on host adaptation in general and of the Bordetella species in particular.